Stroke is the third leading cause of death and disability in adults in the US. Thrombolytic therapy only benefits about 2% of the ischemic stroke patients (Asahi, et al. (2000). Reduction of tissue plasminogen activator induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats. J Cereb Blood Flow Metab 20:452-457). The dismal record of neurorestorative regimens for stroke both in the laboratory and the clinic solicits an urgent need to develop novel therapies. Because the secondary cellular death that ensues after the initial stroke episode occurs over an extended time (Sicard, et al. (2006). Long-term changes of functional MRI-based brain function, behavioral status, and histopathology after transient focal cerebral ischemia in rats. Stroke 37:2593-2600; Virley, et al. (2000). A temporal MRI assessment of neuropathology after transient middle cerebral artery occlusion in the rat: correlations with behavior. J Cereb Blood Flow Metab 20:563-582; Wegener, et al. (2006). Temporal profile of T2-weighted MRI distinguishes between pannecrosis and selective neuronal death after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 26:38-47), treatment strategies directed at rescuing these ischemic neurons have the potential to retard the disease progression and even afford restoration of function (Borlongan C V. (2009). Cell therapy for stroke: remaining issues to address before embarking on clinical trials. Stroke 40(3 Suppl):S146-148; Stem Cell Therapies as an Emerging Paradigm in Stroke Participants. (2009). Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS): bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. Stroke 40:510-515). The recognition of this delay in secondary stroke-induced pathophysiologic alterations has prompted investigations on neurorestorative treatments, including cell therapy, to salvage the ischemic penumbra and promote functional recovery from stroke. Cell therapy thus offers a new avenue for the treatment and management of stroke.
The transplantation of adult stem cells derived from bone marrow has been successfully used in treatment of human disease, such as Fanconi's Anemia, aplastic anemia, acute and chronic leukemias, myeloproliferative disorders, myelodysplatic syndromes, lymphoproliferative disorders, and other malignancies. Alternative sources of bone marrow adult stem cells include peripheral blood progenitor cells, umbilical cord blood and mesenchymal stem cells harvested from these sources. However, there are several shortcomings associated with therapeutic use of adult stem cells. Adult stem cells have been shown to have limited efficacy, such as slow growth and loss of pluripotency after several passages in culture.
Embryonic stem (ES) cells are pluripotent cells that can differentiate to all specialized cell types of the organism (Vescovi & Snyder (1999). Establishment and properties of neural stem cell clones: plasticity in vitro and in vivo. Brain Pathol 9:569-598. Review; Flax, et al. (1998). Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes. Nat Biotechnol 16:1033-1039). Unfortunately, numerous ethical and logistical considerations limit the utility of these cells, which can only be isolated from the inner cell mass of early embryos. Moreover, the tumorigenicity of ES cells remains a major obstacle for clinical application (Casalbore, et al. (2009). Tumorigenic potential of olfactory bulb derived human adult neural stem cells associates with activation of TERT and NOTCH1. PLoS ONE 36 [PubMed—in process]; Kishi, et al. (2008). Variation in the incidence of teratomas after the transplantation of nonhuman primate ES cells into immunodeficient mice. Cell Transplant 17:1095-1102.). The advent of adult stem cells circumvents the inherent problems of ES cells. Although the multipotent property of adult stem cells has been debated, accumulating evidence indicates these cells possess embryonic stem cell-like features including their ability to differentiate into tissues of an entirely different germ layer (Hess & Borlongan (2008). Stem cells and neurological diseases. Cell Prolif 41:94-114; Haas, et al. (2005). Adult stem cell therapy in stroke. Curr Opin Neurol 18:59-64. Review; Chang, et al. (2007). Regenerative therapy for stroke. Cell Transplant 16:171-181; Chopp, et al. (2008). Plasticity and remodeling of brain. J Neurol Sci 265:97-101; Bliss, et al. (2007). Cell transplantation therapy for stroke. Stroke 38:817-826; Kondziolka & Wechsler (2008). Stroke repair with cell transplantation: neuronal cells, neuroprogenitor cells, and stem cells. Neurosurg Focus 24:E13; Garbuzova-Davis, et al. (2006). Novel cell therapy approaches for brain repair. Prog Brain Res 157:207-222).
Effects of the human immune system, the body's inherent mechanism to defend itself from infection and foreign substances, became a critical consideration in early transplants as researchers' encountered illness and/or fatalities resulting from the body's rejection of rejection of cells later characterized as Graft versus Host Disease (GVHD). The bone marrow and umbilical cord blood are the two most studied adult stem cells, and have been proposed for autologous transplantation. The availability of a transplant donor cell type that completely matches the transplant recipient appears as an optimal scenario for cell therapy in view of graft-versus-host complications, in the event of a mismatch between donor and recipient, largely resulting in transplant failure in hematopoietic stem cell transplantation (Remberger, et al. (2007). Major ABO blood group mismatch increases the risk for graft failure after unrelated donor hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 13:675-682; Fleischhauer, et al. (2006). Graft rejection after unrelated donor hematopoietic stem cell transplantation for thalassemia is associated with nonpermissive HLA-DPB1 disparity in host-versus-graft direction. Blood 107:2984-2992). Of interest, immature donor cell sources, such as umbilical cord blood, seem to be relatively tolerated by the transplant recipient despite a HLA mismatch (Laughlin, et al. (2004). Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 351:2265-2275). Accordingly, strategies designed to amplify autologous transplantation should benefit a large patient population. The derivation of adult stem cells from the bone marrow may be painful, whereas harvesting umbilical cord blood is, of course, limited during the baby delivery.
Cell therapy remains an experimental treatment for neurological disorders. The number of cells required for transplant therapies then to be large, whereas only a small, limited number of umbilical cord blood cells can be collected, requiring the umbilical cord blood cells to be expanded prior to use. A major obstacle in pursuing the clinical application of this therapy is finding the optimal cell type that will allow benefit to a large patient population with minimal complications. A cell type that is a complete match of the transplant recipient appears as an optimal scenario. Indeed, the use of autologous bone marrow or umbilical cord blood has been proposed as a good source of stem cells for cell therapy. However, there can be difficulties in promulgating umbilical cord blood cell cultures. Some solutions to these problems include co-culturing umbilical cord blood cells with menstrual blood cells, as described in Walton, et al. (U.S. application Ser. No. 12/290,551).